This application is a 371 of PCT/JP99/06748 filed Dec. 1, 1999, now WO 00/34277 Jun. 15, 2000.
The present invention relates to novel sulfonamide compounds. More particularly, the present invention relates to novel sulfonamide compounds and salts thereof having hypoglycemic activity or PDE-V inhibitory activity. The present invention also relates to a method for producing the above-mentioned sulfonamide compound and salts thereof. Moreover, The present invention relates to pharmaceutical compositions comprising the above-mentioned sulfonamide compound or a salt thereof as an active ingredient.
The present invention aims at providing novel sulfonamide compounds, pharmaceutically acceptable salts thereof and pharmaceutical preparations comprising the above-mentioned sulfonamide compound or a pharmaceutically acceptable salt thereof as an active ingredient, which are used as an agent for the prophylaxis and treatment of impaired glucose tolerance disorder, diabetes (e.g., type II diabetes), gestational diabetes, diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy and the like), insulin resistance syndrome (e.g., insulin receptor abnormality, Rabson-Mendenhall syndrome, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome, Cushing syndrome, acromegaly and the like), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular diseases (e.g., stenocardia, cardiac failure and the like), hyperglycemia (e.g., those characterized by abnormal saccharometabolism such as eating disorders), pancreatitis, osteoporosis, hyperuricemia, hypertension, inflammatory bowel diseases, and skin disorders related to an anomaly of differentiation of epidermic cells; and which, based on the cGMP-PDE (particularly PDE-V) inhibitory action, smooth muscle relaxing action, bronchodilating action, vasodilating action, smooth muscle cell inhibitory action, allergy suppressing action and the like, are used as prophylactic and therapeutic agents for angina pectoris, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis), tubulointerstitial disorders (e.g., kidney diseases induced by FK506, cyclosporin and the like), renal failure, atherosclerosis, angiostenosis (e.g., after percutaneous arterioplasty), peripheral vascular diseases, cerebral apoplexy, chronic reversible obstructive impairment (e.g., bronchitis, asthma inclusive of chronic asthma and allergic asthma), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, diseases characterized by impaired intestinal motility (e.g., irritable bowel syndrome), impotence (e.g., organic impotence, psychic impotence and the like), nephritis, cancer cachexia, restenosis after PTCA, cachexia (e.g., progressive weight loss due to lipolysis, myolysis, anemia, edema, anorexia and the like in chronic diseases such as cancer, tuberculosis, endocrine diseases and AIDS), and the like.
The sulfonamide compound, which is the novel compound of the present invention, is expressed by the formula (I): 
wherein
R1 is an aryl or heterocyclic group substituted by at least one substituent selected from the group consisting of (1) aryl, (2) a heterocyclic group optionally substituted by oxo or halogen, (3) halogen, (4) halo(lower)alkyl, (5) lower alkoxy optionally substituted by cyclo(lower)alkyl, (6) amino optionally substituted by at least one substituent selected from the group consisting of lower alkyl optionally substituted by cyclo(lower)alkyl, protected carboxy, acyl, lower alkylcarbamoyl, and lower alkanesulfonyl, (7) nitro and (8) lower alkynyl optionally substituted by aryl,
R2 is a lower alkyl or lower alkoxy,
R3 is a hydrogen or lower alkyl,
R4 is a lower alkenyl optionally substituted by aryl or heterocyclic group, aryl optionally substituted by carboxy or protected carboxy, lower alkyl optionally substituted by acyloxy, amino optionally substituted by lower alkyl, or heterocyclic group optionally substituted by halogen, and
A is a lower alkylene
[hereinafter to be also referred to as the objective compound (I)].
Preferred salts of the objective compound (I) are conventional salts that are non-toxic and acceptable for use as pharmaceuticals. Examples thereof include salts with alkali metal such as sodium and potassium, salts with alkaline earth metal such as calcium and magnesium, salts with inorganic base such as ammonium salt, salts with organic amine such as triethylamine, pyridine, picoline, ethanolamine and triethanolamine, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, salts with organic carboxylic acid such as formic acid, acetic acid, trifluoroacetic acid, maleic acid and tartaric acid, addition salts with sulfonic acid such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and salts or acid addition salts with base such as basic or acidic amino acid such as arginine, aspartic acid and glutamic acid.
The objective compound (I) and a salt thereof of the present invention can be produced by the method shown by the following reaction formulas.

wherein each symbol in the formula is as defined above.
The objective compound (I) and a salt thereof of the present invention can be also produced by the method shown by the following reaction formulas.

wherein R4a is aryl substituted by at least one protected carboxy, R4b is aryl substituted by at least one carboxy, and other symbols are as defined above.

wherein R1a is aryl or heterocyclic group substituted by at least one amino substituted by at least one protected carboxy, R1b is aryl or heterocyclic group substituted by at least one unsubstituted or monosubstituted amino, and other symbols are as defined above.

wherein Ra is hydrogen or lower alkyl optionally substituted by cyclo(lower)alkyl, R1c is aryl or heterocyclic group substituted by at least one amino substituted by at least one lower alkyl optionally substituted by cyclo(lower)alkyl, and other symbols are as defined above.

wherein R1d is aryl or heterocyclic group substituted by at least one halogen, Rb and Rc are each independently hydrogen, lower alkyl optionally substituted by cyclo(lower)alkyl, protected carboxy, acyl or lower alkanesulfonyl, R1e is aryl or heterocyclic group substituted by at least one amino optionally substituted by at least one substituent selected from the group consisting of lower alkyl optionally substituted by cyclo(lower)alkyl, protected carboxy, acyl and lower alkanesulfonyl, and other symbols are as defined above.

wherein R1f is aryl or heterocyclic group substituted by at least one amino substituted by at least one acyl, and other symbols are as defined above.

wherein each symbol in the formula is as defined above.

wherein R1g is aryl or heterocyclic group substituted by at least one amino substituted by at least one lower alkanesulfonyl, and other symbols are as defined above.
Various definitions included in the entire specification are explained in detail in the following.
xe2x80x9cLowerxe2x80x9d means 1 to 6 carbon atoms, unless otherwise specified.
xe2x80x9cAlkylxe2x80x9d and xe2x80x9calkyl moietyxe2x80x9d are preferably linear or branched alkyl. Specific examples include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, i-butyl, t-butyl, sec-butyl, 1-pentyl, i-pentyl, sec-pentyl, t-pentyl, methylbutyl, 1,1-dimethylpropyl, 1-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl, 1-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 4-ethylpentyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1-propylbutyl, 1-octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 5-ethylhexyl, 1,1-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 5,5-dimethylhexyl, 1-propylpentyl, 2-propylpentyl and the like.
Of these, particularly preferred is alkyl having 1 to 6 carbon atoms.
xe2x80x9cAlkenylxe2x80x9d and xe2x80x9calkenyl moietyxe2x80x9d are preferably exemplified by linear or branched alkenyl, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like.
Of these, preferred is alkenyl having 2 to 6 carbon atoms, which is more preferably ethenyl.
xe2x80x9cCyclo(lower)alkylxe2x80x9d is cycloalkyl having 3 to 10, preferably 3 to 7, carbon atoms. Preferable examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with more preference given to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Examples of preferable lower alkylene include methylene, ethylene, propylene, butylene, pentylene, hexylene and the like, with particular preference given to alkylene having up to 4 carbon atoms. Of these, particularly preferred is methylene.
Examples of preferable lower alkynyl include linear or branched alkynyl, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-butynyl, 1-hexynyl, 5-hexynyl and the like.
Of these, particularly preferred is alkynyl having 2 to 6 carbon atoms, which is more preferably ethynyl.
Lower alkoxy is linear or branched alkyloxy having up to 6 carbon atoms. Prefererable examples thereof include methoxy, ethoxy, 1-propyloxy, i-propyloxy, 1-butyloxy, i-butyloxy, sec-butyloxy, t-butyloxy, 1-pentyloxy, i-pentyloxy, sec-pentyloxy, t-pentyloxy, 2-methylbutoxy, 1-hexyloxy, i-hexyloxy, t-hexyloxy, sec-hexyloxy, 2-methylpentyloxy, 3-methylpentyloxy, 1-ethylbutyloxy, 2-ethylbutyloxy, 1,1-dimethylbutyloxy, 2,2-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethyl-1-methylpropyloxy, and the like.
More preferred is alkoxy having up to 5 carbon atoms, such as methoxy, ethoxy, 1-propyloxy, i-propyloxy, 1-butyloxy, i-butyloxy, sec-butyloxy, t-butyloxy, 1-pentyloxy and the like.
xe2x80x9cLower alkanesulfonylxe2x80x9d is sulfonyl substituted by the above-defined lower alkyl. Preferred is lower alkanesulfonyl having up to 4 carbon atoms, more preferably 1-butanesulfonyl.
Halogen is exemplified by fluorine atom, chlorine atom, bromine atom and iodine atom.
xe2x80x9cHalo(lower)alkylxe2x80x9d is a linear or branched alkyl having up to 6 carbon atoms, which is substituted by fluorine atom, chlorine atom, bromine atom or iodine atom, and is preferably a linear or branched alkyl having up to 6 carbon atoms, which is substituted by fluorine atom, chlorine atom or bromine atom. Examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1,2-difluoroethyl, 1,2-dichloroethyl, 1,2-dibromo-ethyl, 2,2,2-trifluoroethyl, heptafluoroethyl, 1-fluoropropyl, 1-chloropropyl, 1-bromopropyl, 2-fluoropropyl, 2-chloropropyl, 2-bromopropyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 1,2-difluoropropyl, 1,2-dichloropropyl, 1,2-dibromopropyl, 2,3-difluoropropyl, 2,3-dichloropropyl, 2,3-dibromopropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 2-fluorobutyl, 2-chlorobutyl, 2-bromobutyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4,4,4-trifluorobutyl, 2,2,3,3,4,4,4-heptafluorobutyl, perfluorobutyl, 2-fluoropentyl, 2-chloropentyl, 2-bromopentyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, perfluoropentyl, 2-fluorohexyl, 2-chlorohexyl, 2-bromohexyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, perfluorohexyl and the like.
Preferable alkyl of the xe2x80x9clower alkylcarbamoylxe2x80x9d is the above-mentioned lower alkyl.
In the present specification, aryl means unsubstituted aryl or alkyl-substituted aryl. Examples of preferable unsubstituted aryl include C6-C10 aryl, such as phenyl, naphthyl and pentalenyl. Of these, preferred is phenyl and naphthyl.
xe2x80x9cAlkyl-substituted arylxe2x80x9d means aryl substituted by at least one alkyl. The number of alkyl substituents is preferably 1 to 4. The aryl moiety of xe2x80x9calkyl-substituted arylxe2x80x9d is the same as for the aforementioned unsubstituted aryl, and the xe2x80x9calkyl moietyxe2x80x9d is as defined above, which is preferably lower alkyl. Specific examples of preferable alkyl-substituted aryl include tolyl, xylyl, mesityl, ethylphenyl, propylphenyl and the like, with more preference given to p-tolyl.
xe2x80x9cHeterocyclic groupxe2x80x9d is a saturated or unsaturated, heteromonocyclic or heteropolycyclic group having at least one hetero atom, such as oxygen atom, sulfur atom, nitrogen atom and selenium atom. Particularly, unsaturated heteromonocyclic group is preferable. More preferred are the heterocyclic groups described in the below-mentioned (1), (2), (4), (7) and (9), which are still preferably pyridyl, pyrrolyl, pyrrolidinyl, oxazolidinyl, thienyl and furyl.
Heteromonocyclic group includes the following.
(1) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl and 2H-1,2,3-triazolyl), tetrazolyl (e.g., 1H-tetrazolyl and 2H-tetrazolyl) and the like.
(2) Saturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidyl, pyperazinyl and the like.
(3) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,5-oxadiazolyl) and the like.
(4) Saturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolidinyl, thiazolidinyl, morpholinyl, sydnonyl and the like.
(5) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl and 1,2,5-thiadiazolyl), dihydrothiazinyl and the like.
(6) Saturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl and the like.
(7) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having 1 or 2 sulfur atoms, such as thienyl, dihydrodithinyl, dihydrodithionyl and the like.
(8) Saturated 3 to 8-membered (more preferably. 5- or 6-membered) heteromonocyclic group having 1 or 2 oxygen atoms, such as tetrahydrofuryl, tetrahydropyranyl and the like.
(9) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having one oxygen atom, such as furyl and the like.
(10) Spiroheterocyclic group having 1 or 2 oxygen atoms, such as dioxaspiroundecanyl (e.g., 1,5-dioxaspiro[5,5]undecanyl) and the like.
(11) Unsaturated 3 to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group having one oxygen atom and 1 or 2 sulfur atoms, such as dihydroxathinyl.
Examples of heteropolycyclic group include the following.
(12) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1 to 4 nitrogen atoms.
Specific examples thereof include benzimidazolyl, indolyl, 2,3-dihydrobenzimidazolyl, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), tetrahydropyrazolopyrimidinyl (e.g., 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidinyl), imidazopyrazolyl (e.g., 4H-imidazo[1,2-b]pyrazolyl), dihydroimidazopyrazolyl (e.g., 2,3-dihydroimidazo[1,2-b]pyrazolyl), imidazopyridyl (e.g., imidazo[1,5-a] (or [1,2-a] or [3,4-a])pyridyl, 1H (or 3H)-imidazo[4,5-b] (or [4,5-c])pyridyl), pyrrolopyridyl (e.g., 1H-pyrrolo[3,2-b]pyridyl), pyrazolopyridyl (e.g., pyrazolo[1,5-a] (or [2,3-a])pyridyl, 1H (or 2H)-pyrazolo[4,3-b]pyridyl), benzopyrazolyl (e.g., 1H (or 2H)-benzo[c]pyrazolyl), dihydrobenzimidazolyl, benzotriazolyl (e.g., benzo[d][1H-1,2,3]triazolyl), indolidinyl, isoindolyl (e.g., 1H-isoindolyl), indazolyl (e.g., 1H (or 2H or 3H)-indazolyl), indolinyl, isoindolinyl, purinyl, quinolidinyl (e.g., 4H-quinolidinyl), isoquinolyl, quinolyl, phthaladinyl, naphthalidinyl (e.g., 1,8-naphthalidinyl), quinoxalinyl, dihydroquinoxalinyl (e.g., 1,2-dihydroquinoxalinyl), tetrahydroquinoxalinyl (e.g., 1,2,3,4-tetrahydroquinoxalinyl), quinazolinyl, dihydroquinazolinyl (e.g., 1,4 (or 3,4)-dihydro-quinazolinyl), tetrahydroquinazolinyl (e.g., 1,2,3,4-tetrahydro-quinazolinyl), cinnolinyl, pteridinyl, pyrazinopyridazinyl (e.g., pyrazino[2,3-d]pyridazinyl), imidazotriazinyl (e.g., imidazo[1,2-b][1,2,4]triazinyl, imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazinyl), imidazopyrimidine (e.g., 3H-purine and imidazo[1,5-a] (or [3,4-a])pyrimidine), imidazopyridazinyl (e.g., imidazo[2,3-b] (or [3,4-b])pyridazinyl), 1H-1 (or 2)-pyrinedinyl and the like.
(13) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1 to 3 oxygen atoms.
Specific examples thereof include benzofuranyl (e.g., benzo[b] (or [c])furanyl), isobenzofuranyl, furopyridyl, chromenyl (e.g., 2H-chromenyl), chromanyl, isochromanyl, benzoxepinyl (e.g., 3-benzoxepinyl), cyclopentapyranyl (e.g., cyclopenta[b]pyranyl), furopyranyl (e.g., 2H-furo[3,2-b]pyranyl, and the like.
(14) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1 to 3 sulfur atoms.
Specific examples thereof include benzothiophenyl (e.g., benzo[b]thiophenyl), dihydrodithianaphthalenyl (e.g., 4H-1,3-dithianaphthalenyl), dithianaphthalenyl (e.g., 1,4-dithianaphthalenyl) and the like.
(15) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1-to 3 nitrogen atoms and 1 or 2 oxygen atoms.
Specific examples thereof include dioxoloimidazolyl (e.g., 4H-1,3-dioxolo[4,5-d]imidazolyl, benzoxazinyl (e.g., 4H-3,1-benzoxazinyl), pyridoxazinyl (e.g., 5H-pyrid[2,3-d]oxazinyl), pyrazolooxazolyl (e.g., 1H-pyrazolo[4,3-d]oxazolyl), furopyridyl, and the like.
(16) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms.
Specific examples thereof include thienoimidazolyl (e.g., thieno[2,3-d]imidazolyl), thienopyridyl, dithiadiazaindanyl (e.g., 2,3-dithia-1,5-diazaindanyl) and the like.
(17) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1 to 3 oxygen atoms and 1 or 2 sulfur atoms.
Specific examples thereof include thienofuranyl (e.g., thieno[2,3-b]furanyl), and the like.
(18) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1 nitrogen atom, 1 oxygen atom and 1 sulfur atom.
Specific examples thereof include oxathiolopyrrolyl (e.g., 4H[1,3]-oxathiolo[5,4-b]pyrrolyl, and the like.
(19) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1 or 2 selenium atoms.
Preferred specific examples include benzoselenophenyl (e.g., benzo[b] (or [c])selenophenyl), and the like.
(20) Saturated or unsaturated 7 to 12-membered (more preferably 8 to 10-membered) heteropolycyclic (more preferably heterodicyclic) group having 1 or 2 selenium atoms and 1 to 3 nitrogen atoms.
Specific examples thereof include selenopyridyl (e.g., seleno[3,2-b]pyridyl), and the like.
xe2x80x9cAcylxe2x80x9d and xe2x80x9cacyl moietyxe2x80x9d are exemplified by carbamoyl, liphatic acyl, and acyl having heterocyclic group called to as aromatic acyl or acyl having heterocyclic group called to as heterocyclic acyl. Preferable examples of the above-mentioned acyl include carbamoyl; aliphatic acyl such as lower alkanoyl having 1 to 10, preferably 1 to 6, carbon atoms, (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, 3,3-dimethylbutanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl and the like), alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl and the like), butyloxycarbonyl, alkanesulfonyl (e.g., methanesulfonyl, ethanesulfonyl and the like), and alkoxysulfonyl (e.g., methoxysulfonyl and ethoxysulfonyl); aromatic acyl such as aroyl (e.g., benzoyl, toluoyl, naphthoyl and the like), aryl(lower)alkanoyl (e.g., phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyryl, phenylpentanoyl and phenylhexanoyl) and naphthyl(lower)alkanoyl (e.g., naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl)), aryl(lower)alkenoyl (e.g., phenyl(lower)alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl) and naphthyl(lower)alkenoyl (e.g., naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl)), aryl(lower)alkoxycarbonyl (e.g., phenyl(lower)alkoxycarbonyl (e.g., benzyloxycarbonyl)), aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl and the like), aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl and the like), arylcarbamoyl (e.g., phenylcarbamoyl and the like), arylthiocarbamoyl (e.g., phenylthiocarbamoyl and the like), and arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl and the like); heterocyclic acyl such as arenesulfonyl (e.g., benzenesulfonyl and p-toluenesulfonyl), heterocyclecarbonyl; heterocycle(lower)alkanoyl (e.g., thienylacetyl, thienyl-propanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, tetrazolylacetyl and the like), heterocycle(lower)alkenoyl (e.g., heterocyclepropenoyl, heterocyclebutenoyl, heterocyclepentenoyl, heterocyclehexenoyl and the like), and heterocycleglyoxyloyl (e.g., thiazolylglyoxyloyl, thienyl-glyoxyloyl and the like); and the like.
More specifically, the preferable heterocycle moiety of the above-mentioned xe2x80x9cheterocyclecarbonylxe2x80x9d, xe2x80x9cheterocycle(lower)alkanoylxe2x80x9d, xe2x80x9cheterocycle(lower)alkenoylxe2x80x9d and xe2x80x9cheterocycleglyoxyloylxe2x80x9d means a saturated or unsaturated heteromonocyclic or heteropolycyclic group having at least one hetero atom such as oxygen atom, sulfur atom, nitrogen atom and the like, with particular preference given to the heterocyclic groups mentioned above.
The aforementioned acyl moiety may have 1 to 10 same or different suitable substituent(s), such as halogen (e.g., fluorine, chlorine, bromine and iodine), hydroxy, nitro, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl), amino, protected amino, heterocycle(lower)alkylamino having the above-mentioned heterocycle moiety and lower alkyl moiety, lower alkoxy (e.g., methoxy, ethoxy, propoxy, butyloxy, t-butyloxy, pentyloxy and hexyloxy), carboxy, protected carboxy, N,N-di(lower)alkylamino(lower)alkyl (e.g., N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-dipropylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, N,N-dipropylaminoethyl, N,N-dimethylaminopropyl, N,N-diethylaminopropyl, N,N-dipropylaminopropyl, N,N-dibutylaminomethyl, N,N-dipentylaminomethyl and N,N-dihexylaminomethyl), hydroxyimino(lower)alkyl (e.g., hydroxyiminomethyl, hydroxyiminoethyl, hydroxyiminopropyl, hydroxyiminobutyl, hydroxyiminopentyl and hydroxyiminohexyl), arylimino(lower)alkyl exemplified by phenylimino(lower)alkyl (e.g., phenyliminomethyl, phenyliminoethyl, phenyliminopropyl, phenyliminobutyl, phenyliminopentyl and phenyliminohexyl), acyl such as lower alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, pentanoyl and hexanoyl), hydroxy(lower)alkylheterocycle(lower)alkyl having the above-mentioned lower alkyl moiety and heterocycle moiety, mono- (or di- or tri-)halo(lower)alkyl, and arylamino (e.g., phenylamino).
More preferable xe2x80x9cacylxe2x80x9d is the above-mentioned lower alkanoyl.
The preferable acyl moiety of acyloxy is exemplified by acyl moiety defined above, more preferably acetyl.
Preferable example of the protected carboxy is esterified carboxy.
Examples of preferable ester moiety of the esterified carboxy include lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and hexyl ester, and the like. These groups may have at least one appropriate substituent, which is exemplified by lower alkanoyloxy(lower)alkyl ester such as. acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxy-methyl ester, 1 (or 2)-acetoxyethyl ester, 1 (or 2 or 3)-acetoxypropyl ester, 1 (or 2, 3 or 4)-acetoxybutyl ester, 1 (or 2)-propionyloxyethyl ester, 1 (or 2 or 3)-propionyloxypropyl ester, 1 (or 2)-butyryloxyethyl ester, 1 (or 2)-isobutyryloxyethyl ester, 1 (or 2)-pivaloyloxyethyl ester, 1 (or 2)-hexanoyl-oxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2)-pentanoyloxyethyl ester), lower alkanesulfonyl-(lower)alkyl ester (e.g., 2-mesylethyl ester), mono- (or di- or tri-)-halo(lower)alkyl ester (e.g., 2-iodoethyl ester and 2,2,2-trichloroethyl ester), lower alkoxycarbonyloxy(lower)alkyl ester (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester and 1-isopropoxycarbonyloxyethyl ester), phthalidylidene(lower)alkyl ester and (5-lower alkyl-2-oxo-1,3-dioxol-4-yl)(lower)alkyl ester (e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1,3-dioxol-4-yl)methyl ester and (5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester); lower alkenyl ester (e.g., vinyl ester and allyl ester); lower alkynyl ester (e.g., ethynyl ester and propynyl ester); aryl(lower)alkyl ester optionally having at least one suitable substituent, such as mono- (or di- or tri-)phenyl(lower)alkyl ester optionally having at least one suitable substituent, which is exemplified by benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenylethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester and 4-hydroxy-3,5-di-t-butylbenzyl ester; aryl ester optionally having at least one suitable substituent, such as phenyl ester, 4-chlorophenyl ester, tolyl ester, t-butylphenyl ester, xylyl ester, mesityl ester and cumenyl ester; cyclo(lower)alkyl ester (e.g., cyclohexyl ester); phthalidyl ester; and the like.
When the above-mentioned substituents are substituted, the number of the substituents is preferably 1 to 4, unless particularly specified.
Preferable examples of the objective compound (I) are the compound of the formula (I) wherein R1 is pyridyl optionally substituted by at least one substituent selected from the group consisting of (1) aryl, (2) a heterocyclic group, (3) halogen, (4) halo(lower)alkyl, (5)lower alkoxy optionally substituted by cyclo(lower)alkyl, (6) amino optionally substituted by at least one substituent selected from the group consisting of lower alkyl optionally substituted by cyclo(lower)alkyl, and protected carboxy, acyl and lower alkanesulfonyl, (7) nitro, and (8) lower alkynyl optionally substituted by aryl, and a salt thereof.
Of the objective compounds, another particularly preferable compound has the following formula (IA): 
wherein R2 is lower alkyl or lower alkoxy,
R3 is hydrogen or lower alkyl,
R4 is lower alkenyl optionally substituted by aryl or heterocyclic group, aryl optionally substituted by carboxy or protected carboxy, lower alkyl optionally substituted by acyloxy, amino optionally substituted by lower alkyl, or heterocyclic group optionally substituted by halogen,
R5 is pyrrolyl, furyl, or amino substituted by protected carboxy optionally substituted by lower alkyl, and
X is halogen,
and a salt thereof.
Particularly preferable groups are as follows.
R1: 3-chloro-4-biphenylyl, 2-chloro-4-methoxyphenyl, 2-chloro-4-ethoxyphenyl, 2-chloro-4-(1-propoxy)phenyl, 2-chloro-4-isopropoxyphenyl, 2-chloro-4-(1-butoxy)phenyl, 2-chloro-4-(1-pentyloxy)phenyl, 2-chloro-4-((cyclopentylmethyl)oxy)phenyl, 2-chloro-4-ethoxyphenyl, 2-chloro-4-(N-(tert-butoxycarbonyl)-N-methylamino)phenyl, 2-chloro-4-(methylamino)phenyl, 2-chloro-4-(ethylmethylamino)phenyl, 2-chloro-4-(methyl-(1-propyl)amino)-phenyl, 4-(1-butyl)methylamino-2-chlorophenyl, 2-chloro-4-(dimethylamino)phenyl, 2-chloro-4-(ethylmethylamino)phenyl, 2-chloro-4-((1-butyl)methylamino)phenyl, 2-chloro-4-(methyl-(1-pentyl)amino)phenyl, 2-chloro-4-(N-(cyclohexylmethyl)-methylamino)phenyl, 4-bromo-2-chlorophenyl, 3-chloro-5-(trifluoromethyl)-2-pyridyl, 2-chloro-4-(2-furyl)phenyl, 2-chloro-4-(N-(ethoxycarbonyl)-N-methylamino)phenyl, 2-chloro-4-(N-(tert-butoxycarbonyl)-N-ethylamino)phenyl, 2-chloro-4-(N-(pivaloyl)-N-methylamino)phenyl, 2-chloro-4-(ethylamino)phenyl,2-chloro-4-(diethylamino)phenyl, 2-chloro-4-(1-pentylethylamino)-phenyl, 2,6-dichloro-3-pyridyl, 2-chloro-4-(cyclohexylmethyloxy)-phenyl, 2-chloro-4-(1-pyrrolyl)phenyl, (2,4-dichloro-5-nitro)-phenyl, (2,4-dichloro-5-(N,N-dimethylamino))phenyl, (4-(N-(1-butanesulfonyl)-N-methylamino)-2-chlorophenyl, 2-chloro-4-(N-methyl-N-(1-propoxycarbonyl)amino)phenyl, 2-chloro-4-(N-methyl-N-(isopropoxycarbonyl)amino)phenyl, 4-(N-(tert-butoxycarbonyl)-amino)-2-chlorophenyl, 2-chloro-4-(ethoxycarbonylamino)phenyl, 2-chloro-4-(N-valerylamino)phenyl, 4-(N-(1-butanesulfonyl)amino)-2-chlorophenyl, 2-chloro-4-(N-(t-butylacetyl)amino)phenyl,
R2: methyl, ethyl, ethoxy,
R3: hydrogen, methyl,
R4: (E)-2-(4-pyridyl)vinyl, 1-pentyl, 1-butyl, 4-methylphenyl, 1-propylamino, 1-butylamino, (E)-2-(phenyl)vinyl, 5-bromo-2-thienyl, 5-chloro-2-thienyl, 4-ethoxycarbonylphenyl, 4-carboxyphenyl, 4-acetoxybutyl,
R5: N-(tert-butoxycarbonyl)-N-methylamino, 2-furyl, N-(ethoxycarbonyl)-N-methylamino, N-(tert-butoxycarbonyl)-N-ethylamino, 1-pyrrolyl, N-methyl-N-(isopropoxycarbonyl)amino, N-methyl-N-(isopropoxycarbonyl) amino, N-(tert-butoxycarbonyl)amino, ethoxycarbonylamino,
A: methylene,
X: chlorine.
Preferable objective compounds (I) are as follows.
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(E)-[2-(4-pyridyl)ethene]sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 5-[(4-acetoxybutane)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-ethoxycarbonylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-carboxybenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-methoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-methoxybenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-ethoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-ethoxybenzyl)-2-methyl-5-((1-propylaminosulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine, 5-((1-butylaminosulfonyl)carbamoyl)-3-(2-chloro-4-ethoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-propoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-isopropoxybenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-isopropoxybenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-butoxy)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-5-((E)-(2-phenylethene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine, 3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(5-chlorothiophen-2-yl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 5-((1-propylaminosulfonyl)carbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 5-((1-butylaminosulfonyl)carbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-((cyclopentylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-ethoxybenzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-ethoxybenzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-propoxy)benzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(1-propoxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-propoxy)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine, 3-[2-chloro-4-(1-pentyloxy)benzyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(methyl-(1-propyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-((1-butyl)methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(dimethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(ethylmethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(methyl-(1-propyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-((1-butyl)methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(methyl-(1-pentyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-(cyclohexylmethyl)methylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl)-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(ethylmethylamino)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-phenylbenzyl)-2-ethoxy-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(1-propylaminosulfonyl)carbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[(3-chloro-5-(trifluoromethyl)-2-pyridyl)methyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(2,6-dichloro-3-pyridyl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(methyl(pivaloyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(1-pentyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2-ethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine, 3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[2-chloro-4-(2-furyl)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(ethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N,N-diethylamino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-ethyl-N-(1-pentyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(methylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-methyl-N-propylamino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl]-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(1-pyrrolyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[2-chloro-4-(cyclohexylmethyloxy)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine sodium salt, 3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[2-chloro-4-(2-furyl)benzyl]-2,7-dimethyl-5-(1-butanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2,4-dichloro-5-nitrobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2,4-dichloro-5-nitrobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[2,4-dichloro-5-(N,N-dimethylamino)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(1-butanesulfonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine sodium salt, 3-(2-chloro-4-(N-methyl-N-(1-propoxycarbonyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-methyl-N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(tert-butoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(ethoxycarbonylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-valerylamino)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(1-butanesulfonyl)amino)-2-chlorobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-(t-butylacetyl)amino)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(N-(isopropoxycarbonyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(2-chloro-4-(N-ethoxycarbonyl-N-methylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine,3-(4-amino-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(1-propoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(isopropoxycarbonyl)amino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 5-(1-butanesulfonylcarbamoyl)-3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(4-amino-2-chlorobenzyl)-5-(1-butanesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine, 3-(4-ethoxycarbonylamino-2-chlorobenzyl)-2-methyl-5-(1-butanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-t-butoxycarbonylamino)-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-amino-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-ethoxycarbonylamino-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(3-(1-propyl)ureido)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-(4-(1-methyl-3-(1-propyl)ureido)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(2-oxo-1-pyrrolidinyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(2-oxo-1,3-oxazolidin-3-yl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(((2-(4-methylbenzene)sulfonylcarbamoyloxy)-ethyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(4-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-((6-chloro-1,2-dimethyl-1H-benzimidazol-5-yl)methyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(3,5-dichloropyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-5-((4-methylbenzenesulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine, 3-((3,5-dichloropyridin-2-yl)methyl)-2,7-dimethyl-5-(((E)-2-phenylethenesulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(2-chloro-6-phenylpyridin-3-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(5-(N-(tert-butoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(3-chloro-5-(N-(ethoxycarbonyl)amino)pyridin-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine, 3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((E)-1-penten-1-ylsulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-[(5-(N-(isopropoxycarbonyl)amino)-3-chloropyridin-2-yl)methyl]-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-((2,4-dichloropyridin-5-yl)methyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, 3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine sodium salt, 3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine sodium salt, 3-(2-chloro-4-(phenylethynyl)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine sodium salt, 5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine sodium salt, 3-[2-chloro-4-(1-pentyloxy)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine sodium salt, 3-(4-(N-(ethoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine, and 3-(4-(N-(benzyloxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine.
The production methods of the objective compound (I) are explained in detail in the following.
The objective compound (I) and a salt thereof can be produced by reacting compound (II) or reactive derivative at carboxy thereof or a salt thereof with compound (III) or a salt thereof.
Preferable salts of compound (II), reactive derivative at carboxy thereof and compound (III) are exemplified by those shown with regard to compound (I).
Preferable reactive derivative at carboxy of compound (II) indludes acid halide, acid anhydride inclusive of intramolecular acid anhydride, intermolecular acid anhydride and mixed acid anhydride, active amide, active ester and the like. Preferable examples thereof include acid chloride, acid azide, mixed acid anhydride with acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid and halogenated phosphoric acid), dialklphosphinic acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (e.g., methanesulfonic acid), aliphatic carboxylic acid (e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid and trichloroacetic acid), aromatic carboxylic acid (e.g., benzoic acid), and the like; symmetric acid anhydride; active amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; active ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N+xe2x95x90CHxe2x80x94] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester, p-nitrophenylthio ester, p-cresylthio ester, carboxymethylthio ester, pyranyl ester, pyridyl ester, piperidyl ester and 8-quinolylthio ester); esters with N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-1H-pyridone, N-hydroxysuccinimide and 1-hydroxy-1H-benzotriazole); and the like. These reactive derivatives can be appropriately selected according to the kind of compound (II) to be used.
The reaction generally proceeds in a conventional solvent such as water, alcohol (e.g., methanol and ethanol), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine and a mixture thereof, or in any other solvent which does not adversely affect the reaction. These conventional solvents may be used alone or in combination.
When compound (II) is used in the form of a free acid or a salt thereof in this reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide, N-cyclohexyl-Nxe2x80x2-morpholinoethylcarbodiimide, N-cyclohexyl-Nxe2x80x2-(4-diethylaminocyclohexyl)carbodiimide, N,Nxe2x80x2-diethylcarbodiimide, N,Nxe2x80x2-diisopropylcarbodiimide, N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide, N,Nxe2x80x2-carbonylbis(2-methyl-imidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphorate, isopropyl polyphosphate, phosphorous oxychloride (phosphoryl chloride), phosphorus trichloride, diphenylphosphoryl azide, diphenyl chlorophosphate, diphenylphosphinic chloride, thionyl chloride, oxalyl chloride, lower alkyl haloformate (e.g., ethyl chloroformate and isopropyl chloroformate), triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, intramolecular salt of 2-ethyl-5-(m-sulfophenyl)-isoxazolium hydroxide, 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, and so-called Vilsmeier reagent (prepared by the reaction of N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorous oxychloride, or the like), and the like.
The reaction can be carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate, tri(lower)alkylamine, pyridine, 4-dimethylaminopyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylaniline (e.g., N,N-dimethylaniline), N,N-di(lower)alkylbenzylamine, and the like.
The reaction temperature is not particularly limited, and the reaction is generally carried out under cooling to heating.
The objective compound (I-b) and a salt thereof can be produced by subjecting compound (I-a) or a salt thereof to elimination of carboxy-protecting group.
The preferable salts of compound (I-a) and (I-b) are exemplified by those shown with regard to compound (I).
This reaction is carried out according to a conventional method such as hydrolysis and the like.
Hydrolysis is preferably carried out in the presence of a base or an acid inclusive of Lewis acid. Examples of preferable base include inorganic base and organic base such as alkali metal (e.g., lithium, sodium, potassium and the like), alkaline earth metal (magnesium, calcium and the like), and hydroxide, carbonate and bicarbonate thereof, trialkylamine (e.g., trimethylamine, triethylamine and the like), picoline, 1,5-diazabicyclo-[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like. Preferable acid includes organic acid (e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid and the like), inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and the like) and Lewis acid (boron tribromide and the like).
The reaction generally proceeds in a solvent such as water, alcohol (e.g., methanol, ethanol and the like), xylene, diethyleneglycol monomethyl ether, methylene chloride, tetrahydrofuran, mixtures thereof and the like, or any other solvent that does not adversely affect the reaction. A liquid base or acid can be also used as a solvent. The reaction temperature is not particularly limited and the reaction generally proceeds under cooling to heating.
Compound (I-d) and a salt thereof can be produced by subjecting compound (I-c) or a salt thereof to elimination of amino-protecting group.
The preferable salts of compound (I-c) and (I-d) are exemplified by those shown with regard to compound (I).
This reaction can be carried out in essentially the same manner as in Production Method 2, and therefore, the method of reaction and reaction conditions (e.g., solvent, reaction temperature and the like) are to be referred to those disclosed for Production Method 2.
The objective compound (I-e) and a salt thereof can be prepared by adding compound (IV) to compound (I-d) or a salt thereof by reduction.
The preferable salts of compound (I-d) and (I-e) are exemplified by those shown with regard to compound (I).
The reduction can be carried out in chemical reduction and catalytic reduction, which may be carried out by a conventional method.
The preferable reducing agent used in the chemical reduction is, for example, metal such as tin, zinc and iron, a combination of such a metal and/or a metal compound such as chromium chloride and chromium acetate, and an organic acid or inorganic acid such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid and hydrobromic acid, a combination of the aforementioned metal and/or metal compound and a base (e.g., ammonia, ammonium chloride, sodium hydroxide and the like), metal hydride compound such as aluminum hydride compound (e.g., lithium aluminum hydride, alminium sodium hydride, aluminum hydride, trimethoxy aluminum lithium hydride, tri-t-butoxy aluminum hydride and the like), borohydride compound (e.g., sodium borohydride, lithium borohydride, sodium cyanoborohydride, tetramethyl ammonium borohydride, borane, diborane and the like) and the like, phosphorus compound (phosphorus trichloride, phosphorus tribromide, triphenylphosphine, triethylphosphine and the like) and the like.
The preferable reducing agent used in the catalytic reduction is conventional one, for example, platinum catalyst such as platinum plate, platinum sponge, platinum black, platinum colloid, platinum oxide and platinum wire, palladium catalyst such as palladium sponge, palladium black, palladium oxide, palladium carbon, palladium colloid, palladium-barium sulfate and palladium-barium carbonate, nickel catalyst such as reduing nickel, nickel oxide and Raney nickel, cobalt catalyst such as reducing cobalt and Raney cobalt, iron catalyst such as reducing iron and Raney iron, copper catalyst such as reducing copper, Raney copper and Ullmann copper, and the like.
The reducion is generally carried out in a solvent. Examples of the solvent used include conventional solvent such as water, alcohol (e.g., methanol, ethanol, propanol and the like), acetonitrile, diethyl ether, dioxane, N,N-dimethylformamide, tetrahydrofuran, liquid base or acid, and a mixed solvent thereof, and any other solvents that do not adversely affect the reaction. A liquid base or acid can be also used as a solvent. The reaction temperature is not particularly limited and the reaction generally proceeds under cooling to heating.
The objective compound (I-g) and a salt thereof can be produced by substituting the halogen of compound (I-f) or a salt thereof with compound (V).
The preferable salts of compound (I-f) and (I-g) are exemplified by those shown with regard to compound (I).
This reaction is preferably carried out in the presence of potassium tert-butylate or a base such as the above-mentioned inorganic or organic base. The reaction is preferably carried out in the presence of a catalyst such as tris(dibenzilideneacetone)-dipalladium(O), (R)-(+)-BINAP [2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl] and the like.
While the reaction temperature is not particularly limited, the reaction is preferably carried out from under room temperature to heating, and the reaction can be also carried out in the presence of a solvent such as toluene, which does not adversely affect the reaction.
The objective compound (I-h) and a salt thereof can be produced by acylation of compound (I-d) or a salt thereof.
The preferable salts of compound (I-f) are exemplified by those shown with regard to compound (I).
When objective compound (I-f) is to be obtained by acylation, compound (I-d) having terminal amino is reacted with an acylating agent. Examples of the acylating agent include lower alkanecarbonyl halide (e.g., pivaloyl chloride) and lower alkanecarbonic anhydride. The solvent may be dichloromethane, tetrahydrofuran and the like, and the reaction proceeds from under ice-cooling to room temperature.
The objective compound (I-c) and a salt thereof can be produced by introducing an amino-protecting group into compound (I-d) or a salt thereof
Examples of the amino-protecting group include halogenated lower alkanecarbonate derivative (e.g., ethyl chlorocarbonate) and lower alkanecarbonic anhydride. The solvent may be dichloromethane, tetrahydrofuran and the like, and the reaction proceeds from under ice-cooling to room temperature.
The objective compound (I-i) and a salt thereof can be produced by sulfonamidation of compound (I-d) or a salt thereof.
The preferable salts of compound (I-i) are exemplified by those shown with regard to compound (I).
When the objective compound (I-i) is obtained by sulfonamidation, compound (I-d) having terminal amino is reacted with lower alkanesulfonyl halide (e.g., butanesulfonyl chloride), lower alkanesulfonic anhydride and the like. The solvent may be dichloromethane, tetrahydrofuran and the like, and the reaction proceeds from under ice-cooling to room temperature.
The aforementioned compounds can be converted to preferable salts as necessary by a conventional method (e.g., the method described in Example 85 to be mentioned later). All of them can be purified as necessary according to a conventional method for purifying an organic compound (i.e., recrystallization, column chromatography, thin layer chromatography, high performance liquid chromatography and the like). The compound can be identified by NMR spectrum analysis, mass spectrum analysis, IR spectrum analysis, elemental anlysis, melting point measurement and the like.
The compound of the present invention may have one or more chrial centers and, therefore, may be presented in enantiomers or diastereomers. Some compounds having alkenyl may be present as a cis or trans isomer. In bose case, the present invention encompasses mixtures thereof and respective isomers.
The inventive compound and a salt thereof may be in the form of a solvate, which is also encompassed in the present invention. The solvate is preferably exemplified by hydrate and ethanol solvate.
The pharmaceutical data of compound (I) are shown in the following to demonstrate the utility of the objective compound (I).
Test Compound
Female C57BL/KsJ-dbm db+/db+, C57BL/KsJ-dbm +m/+m (Jackson Laboratory) mice (5 weeks old) were purchased and subjected to the test after 2-3 weeks of acclimating period.
The test drug was mixed with a powder diet (CE-2, Clea Japan, Inc.) in a mortar. In the case of administration in 100 mg/kg, the mixing proportion was 0.1%, in the case of 30 mg/kg, the proportion was 0.03% and in the case of 10 mg/kg, the proportion was 0.01%. The diet was changed twice a week for each group. The amount of the diet given and the amount left were recorded and the diet intake was calculated by determining the difference.
The female db/db mice were grouped according to body weight, blood sugar level and triglyceride concentration in plasma. Then, the drug-mixed diet was given for 14 days, during which period the mice were 8 to 10 weeks of age. At day 7 and day 14 in the morning, blood was taken from orbital venous plexus using a heparinized glass capillary tube (Chase Heparinized Capillary Tube), and centrifuged to give plasma fractions. The blood sugar level, triglyceride concentration in plasma and insulin concentration in plasma were measured at day 0 and day 14, and blood sugar level and triglyceride concentration in blood were measured at day 7. Body weight was measured at day 0, day 7 and day 14. After final blood sampling, the mice were sacrificed with CO2 gas.
Blood sugar level was measured using 10-15 xcexcl of plasma and in accordance with glucose oxidase method (glucose CII-Test Wako, Wako Pure Chemicals Co., Ltd.). The triglyceride concentration in plasma was measured using 10-15 xcexcl of plasma and in accordance with GPO-p-chlorophenol method (triglyceride G-Test Wako) or GPO-DAOS method (triglyceride E-Test Wako). The measurement was done promptly after blood sampling. The insulin concentration in plasma was measured using 20 xcexcl of plasma (preservable at xe2x88x9220xc2x0 C.) and in accordance with an antibody method (Phadesef Insulin RIA kit, Kabi Pharmacia).
Using the difference between db/db mice control group and +/+ mice in blood sugar level and triglyceride concentration in plasma as 100%, the proportion (%) of decrease in the blood sugar level and triglyceride concentration in plasma of the group administered with the test drug was determined. The results are shown in Table 1.
The compound (I) of the present invention can be used for therapeutic purposes in the form of a pharmaceutical preparation. This pharmaceutical preparation contains any one of the compounds (I) as an active ingredient in admixture with a pharmaceutically acceptable organic or inorganic excipient which is a solid, semi-solid or liquid and which is suitable for oral, parenteral or external (local) administration. Examples of the pharmaceutical preparation include capsules, tablets, sugar coating tablets, granules, suppositories, liquid, lotion, suspension,. emulsion, ointment, gel and the like. When desired, these preparations may contain adjuvant, auxiliary substance, stabilizer, moistening agent, emulsifier, buffering agent, and other conventional additives. While the dose of the compound (I) varies depending on the age and symptom of patients, compound (I) may be administered for the therapy of the above-mentioned diseases in an average single dose amount of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg or 1000 mg. In general, its daily dose may be about 0.1 mg/patient to about 1000 mg/patient.